Obesity and related metabolic disorders have become a tremendous public health problem. This proposal investigates the neural circuitry that integrates input from the adiposity hormone leptin and the gut-derived satiety signals cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and the physiological relevance of the interactions between these signals for the control of food intake and body weight. Available data support the hypothesis that the adiposity hormone leptin reduces food intake in part by enhancing satiety responses to gastrointestinal signals, including CCK. We have recently determined that leptin interacts in a similar manner with GLP-1, but our data suggest that the leptin-CCK and leptin-GLP-1 interactions are mediated through different neuronal pathways. Here, we propose to identify and compare brain areas in which leptin detection is sufficient to enhance the responses to GLP-1 and CCK, using site-specific microinjections and gene therapy in normal rats and rats that lack leptin receptors due to genetic mutation. Next, we will investigate whether leptin reduces food intake and enhances the satiety response to gastrointestinal nutrients in part by modulating rats'sensitivity to endogenously released GLP-1 or CCK. Finally, we will determine whether altered sensitivity to GLP-1 or CCK plays a role in the pathogenesis of diet-induced obesity when rats are maintained on a high-fat diet, which produces leptin resistance. Together, these studies will help to clarify how changes in body fat stores lead to compensatory adjustments in meal size, as well as how defects in this process may lead to obesity and metabolic disorders, and thus have the potential to significantly advance our understanding of the neural control of feeding and body weight. Lay Description: This research focuses on how the brain detects stored energy in fat along with the presence of nutrients in the gut, and then integrates that information to determine how much food to eat. Specifically, we will examine the brain areas that mediate these effects, as well as the relevance of these interactions to normal control of feeding and the development of obesity. Our studies will improve our understanding of the neural circuitry that regulates food intake and body weight, and will help identify biological factors that contribute to the development and maintenance of obesity.